ES2206065B1 - PROCEDURE FOR OBTAINING THE POLYMORPHIC FORM I OF FINASTERIDA. - Google Patents

Abstract

Procedure for obtaining the form polymorphic I of finasteride.

The process comprises (i) dissolving finasteride in a substantially anhydrous organic solvent, selected from n-butyl acetate, acetate iso-butyl, sec-butyl acetate, tert-butyl acetate, C5 alkyl acetate, and mixtures thereof, at a temperature equal to or less than the point of boiling said organic solvent; (ii) cool slowly said finasteride solution up to a temperature of cooling determined according to the solvent chosen; (iii) keep the resulting suspension at cooling temperature for a period of time equal to or less than 16 hours; and (iv) recover the solid phase that contains the crystals of Form 1 of finasteride, for example, by filtration, and removing the solvent, for example, by drying said crystals. He procedure allows to obtain a unique and pure form 1 of Finasteride

Description

Procedure for obtaining the form polymorphic I of finasteride.

Field of the Invention

The invention relates to a process for obtaining the pure polymorphic form of finasteride called Form I.

Background of the invention

Finasteride [(5α, 17?) -N- (1,1-dimethylethyl) -3-oxo-4-aza-androst- 1-eno-17-carboxamide] It is an inhibitor of 5- α-reductase, enzyme that reduces testosterone to dihydrotestosterone (DHT) which is the main mediator of androgenic activity in some organs. Finasteride can prevent or reduce the symptoms of hyperandrogenic stimulation and is used as an active ingredient in multiple therapeutic applications, for example, in treatment of benign prostatic hyperplasia and alopecia Androgenic

Several procedures are known for obtaining finasteride [see, for example, patents US 4,377,584, US 4,760,071, US 5,084,574, US 5,116,983 or patent application WO 01/02422].

Finasteride can exist in several forms different polymorphs [see, for example, European patent EP 0 599 376 B1, patent application WO 02/20553 Al or the scientific publication Journal of Molecular Structure, 474, (1999), 157-166], among which are the called Form I and Form II, which differ from each other in their crystal structure The different crystalline structures that may present a compound lead to a variation in their physicochemical parameters, such as, for example, stability, dissolution rate, solubility, melting point, etc. This variation in the properties of the compound translates into a different bioavailability of it, especially in those cases in which the active substance is supplied from solid form.

From the pharmaceutical point of view it is very important to have unique and pure crystalline forms for the development of pure pharmaceutical forms that meet the Required specifications of pure pharmaceutical product. The obtaining unique crystalline forms solves the problems of lack of reproducibility and bioavailability different than present the pharmaceutical forms when mixtures of polymorphs The different polymorphic forms can be obtained controlling the crystallization conditions.

In the particular case of finasteride, the form Polymorphic marketed is Form I, which constitutes the active principle of the pharmaceutical specialty called Proscar®.

In US Patents 5,652,365 and EP 0 599 376 B1 describes the preparation of polymorphic forms Form I and Form Finasteride II. In particular, EP 0 599 376 B1 claims a procedure for obtaining Form I of finasteride that comprises the crystallization of said Form I from acetate of ethyl with a water content of up to 3.5 mg / mL or from Isopropyl acetate with a water content of up to 1.6 mg / mL at room temperature.

GB 2,338,234 describes a process for the preparation of Form I of finasteride comprising initially form a substantially insoluble complex formed by finasteride and a salt of a metal of Group I or Group II of the periodic table of elements, such as lithium bromide, in presence of a hydroxylic solvent, followed by dissociation of the complex by dissolution with acidified water and recovery of the Crystalline form of finasteride.

Compendium of the invention

It is, therefore, object of the present invention, provide an alternative procedure for obtaining finasteride in its pharmaceutically desirable form, that is, in its polymorphic form I (Form I).

The procedure for obtaining Form I of Finasteride provided by the present invention is based on the fact that the inventors have observed that dissolving finasteride, in hot, in a substantially anhydrous organic solvent, selected from n-butyl acetate, acetate iso-butyl, sec-butyl acetate, tert-butyl acetate, C5 alkyl acetate, and mixtures thereof, at a temperature equal to or less than the point of boiling said organic solvent, slowly cooling said solution up to a certain temperature depending on the chosen solvent and maintaining the temperature reached during a determined period of time, crystals of said Form are obtained I of finasteride that can be easily recovered from the waters Crystallization mothers.

The procedure provided by this invention allows to obtain in a unique and pure way the Form I of finasteride without appear quantifiable signals of Form II and with a performance high.

Detailed description of the invention

The invention provides a method for obtaining the polymorphic form of finasteride called Form I which comprises the following stages:

to)

dissolve finasteride in a solvent organic, substantially anhydrous, selected from acetate n-butyl, iso-butyl acetate, sec-butyl acetate, tert-butyl acetate, C5 alkyl acetate, and mixtures thereof, at an equal temperature or less than the boiling point of said solvent organic;

b)

cool finasteride solution obtained in stage a) until:

(i)

a cooling temperature between 20 ° C and 45 ° C, with a cooling rate between 0.1 ° C / min and less than 2 ° C / min, when said organic solvent is acetate n-butyl, iso-butyl acetate, sec-butyl acetate or acetate tert-butyl; Or until

(ii)

a cooling temperature between 0 ° C and 45 ° C, with a cooling rate between 0.1 ° C / min and less than 2 ° C / min, when said organic solvent is alkyl acetate C5; Y

c) maintain the suspension resulting from the stage b) at the cooling temperature for a period of time equal to or less than 16 hours, optionally with stirring, and

d) recover the resulting solid phase that contains Form I finasteride, and remove the solvent.

In accordance with the present invention, the finasteride, which can be obtained by any of the known procedures [see Background of the Invention], it is dissolved in an organic solvent selected from acetate n-butyl, iso-butyl acetate, sec-butyl acetate, acetate tert-butyl, C5 alkyl acetate, and their mixtures The term "C5 alkyl", as used in This description refers to an alkyl group, linear or branched, of 5 carbon atoms, for example, isoamyl.

Said organic solvent is substantially anhydrous, that is, its water content is equal to or less than 0.08% (w / w). Preferably, said solvent is completely lacking of water or has a minimum water content since the presence of water favors the formation of the polymorphic form of finasteride known as Form II.

The solution of finasteride in the solvent selected is favored by heating the finasteride in said solvent to the boiling point of the solvent, generally, between 80 ° C and 140 ° C. In a particular embodiment, when the solvent chosen is acetate n-butyl or iso-butyl acetate, the solution of finasteride in said solvent is favored heating the mixture at a temperature between 100 ° C and 120 ° C In another particular embodiment, when the solvent chosen is tert-butyl acetate, said dissolution is favored by heating the mixture at a temperature between 90 ° C and 100 ° C. In another particular embodiment, when the solvent chosen is isoamyl acetate, the finasteride solution in said solvent is favored heating the mixture at a temperature between 125 ° C and 140 ° C

Depending on the solvent chosen, the solution Hot finasteride slowly cools to:

(i)

a cooling temperature between 20 ° C and 45 ° C, with a cooling rate between 0.1 ° C / min and less than 2 ° C / min, preferably between 0.2 ° C / min and 1.3 ° C / min, more preferably between 0.3 ° C / min and 0.5 ° C / min, when said organic solvent is n-butyl acetate, acetate of iso-butyl, sec-butyl acetate or tert-butyl acetate; Or until

(ii)

a cooling temperature between 0 ° C and 45 ° C, with a cooling rate between 0.1 ° C / min and less than 2 ° C / min, preferably between 0.2 ° C / min and 1.3 ° C / mirr, when said Organic solvent is C5 alkyl acetate.

At these cooling temperatures, in the conditions indicated, the formation of crystals of the Form I of finasteride. This cooling stage of the Finasteride solution can optionally be carried out with stirring, for example, between 30 rpm and 800 rpm, preferably with a stirring speed between 60 rpm and 300 rpm. The resulting finasteride suspension is kept at the temperature cooling for a period of time equal to or less than 16 hours, preferably between 1 and 6 hours.

In a particular embodiment, using as solvent n-butyl acetate or acetate iso-butyl, the cooling of the solution of hot finasteride, at a temperature between 100 ° C and 120 ° C, is performed with stirring, at a cooling rate between 0.2 ° C / minute and 1.3 ° C / minute, up to cooling temperature between 20 ° C and 45 ° C, and maintains the temperature reached over a period of time between 1 and 3 hours.

In another particular embodiment, using as tert-butyl acetate solvent, cooling of the hot finasteride solution, at a temperature between 90 ° C and 100 ° C, it is done with stirring, at a cooling rate between 0.2 ° C / minute and 1.3 ° C / minute, up to a cooling temperature included between 20 ° C and 45 ° C, and the temperature reached during a period of time between 1 and 16 hours.

In another particular embodiment, using as Isoamyl acetate solvent, cooling the solution of hot finasteride, at a temperature between 120 ° C and 140 ° C, is performed with stirring, at a cooling rate between 0.2 ° C / minute and 1.3 ° C / minute, up to cooling temperature between 0 ° C and 45 ° C, and maintains the temperature reached over a period of time between 1 and 3 hours.

Form I crystals of finasteride formed can be recovered from the crystallization mother liquor by any conventional method, for example, by any solid / liquid separation technique. In one embodiment in particular, the crystals of the formed I form of finasteride are they separate from the mother liquor from crystallization by filtration. The recovery of Form I crystals of finasteride is performed, in general, at the temperature at which the finasteride solution It has been cooled.

Form I of finasteride thus obtained, if you want, you can undergo a drying process in order to remove the solvent. Said drying can be done using any conventional method and equipment combining temperature and drying time. In a particular embodiment, Form I of finasteride obtained according to the procedure provided by this invention is subjected to a vacuum drying process to a temperature of 60 ° C.

If desired, the procedure provided by This invention includes a step of concentration of the solution of finasteride before proceeding with the recovery of the crystals of Form I of finasteride. The concentration of said solution of Finasteride can be performed by any conventional method. In a particular embodiment, the concentration of the solution of Finasteride is performed hot, under vacuum, before proceeding to its cooling.

Form I of finasteride obtained according to procedure provided by the present invention can be identify and characterize by differential scanning calorimetry (DSC), X-ray diffraction analysis (DRX) and spectroscopy of infrared (IR).

The data obtained and described in Example 1.3 allow unambiguously identify the crystalline form obtained from finasteride as pure Form I when compared to described in European patent EP 0 599 376 B1.

According to the information provided in said patent European EP 0 599 376 B1, the characteristics of Form I of Finasteride are as follows:

a curve of differential scanning calorimetry (DSC), performed in capsule closed and with a heating rate of 20 ° C / min, which shows a peak with a small endotherm above 232 ° C, extrapolated at baseline of 223 ° C with an associated heat of 11 J / g, and a 261 ° C main fusion endotherm, extrapolated to baseline 258 ° C with an associated heat of 89 J / g;

the diffractogram X-ray powder (DRX) shows signals with spacing units baseline of 6.44, 5.69, 5.36, 4.89, 4.55, 4.31, 3.85, 3.59 and 3.14;

the spectrum of Fourier transform infrared (FT-IR), made in KBr tablet, shows some characteristic bands to 3431, 3237, 1692, 1666, 1602 and 688 cm -1; Y

the Water and cyclohexane solubilities at 25 ° C are respectively 0.05 ± 0.02 and 0.27 ± 0.05 mg / g.

On the other hand, the characteristics of finasteride Form II are the following:

a curve of differential scanning calorimetry (DSC), performed in capsule closed and with a heating rate of 20 ° C / min, which shows a single fusion endotherm of 261 ° C, extrapolated to baseline of 258 ° C with an associated heat of 89 J / g;

the diffractogram X-ray powder (DRX) shows signals with spacing units Baseline of 14.09, 10.36, 7.92, 7.18, 6.40, 5.93, 5.66, 5.31, 4.68, 3.90, 3.60 and 3.25;

the spectrum of Fourier transform infrared (FT-IR), made in KBr pads, shows some characteristic bands at 3441, 3215, 1678, 1654, 1597, 1476 and 752 cm <-1>; Y

the Water and cyclohexane solubilities at 25 ° C are respectively 0.16 ± 0.02 and 0.42 ± 0.05 mg / g.

The procedure provided by this invention It is simple, reproducible and allows to obtain unique and pure Form I of finasteride. Unlike other procedures known to obtain Form I of finasteride, allows to obtain high yield of finasteride Form 1, uniquely and pure, which constitutes an important advantage at the level industrial.

The following examples illustrate the invention and They should not be considered as limiting it. In sayings examples highlights the importance of controlling the solvent, cooling temperature and speed of cooling of the finasteride solution.

Examples 1-9 illustrate the obtaining pure Form I of finasteride using acetate n-butyl as solvent and slowly cooling the finasteride solution up to a temperature between 25 ° C and 45 ° C. On the contrary, Examples 10 and 11 put manifest that when the solvent chosen is acetate of n-butyl and cooling of the solution d e Finasteride is performed slowly to a temperature of 0 ° C (Example 10) or quickly up to a temperature of 25 ° C (Example 11) a mixture of crystalline forms of Finasteride

Example 12 illustrates the obtaining of Form I pure finasteride using acetate iso-butyl as solvent and slowly cooling the finasteride solution to a temperature of 25 ° C. Without However, when a solution of finasteride in acetate iso-butyl is cooled slowly to a temperature of 0 ° C (Example 19) a mixture of forms is obtained crystals of finasteride.

Example 13 illustrates obtaining Form 1 pure finasteride using isoamyl acetate as solvent and slowly cooling the finasteride solution to a temperature of 0 ° C.

Example 14 illustrates obtaining Form 1 pure finasteride using acetate tert-butyl as solvent and slowly cooling finasteride solution to a temperature of 25 ° C. Without However, when dissolving finasteride in acetate tert-butylose slowly cools to a temperature of 0 ° C (Example 16) a mixture of forms is obtained crystals of finasteride.

Example 15 shows that the use of methyl acetate as solvent and slow cooling of the finasteride solution up to a temperature of 25 ° C does not allow obtain Form I of finasteride.

Examples 17 and 18 show that dissolving finasteride in n-propyl acetate and slowly cooling the finasteride solution until temperatures of 0 ° C or 25 ° C a mixture of forms is obtained crystals of finasteride.

Example 1 Obtaining Form I of Finasteride 1.1 Obtaining finasteride

Raw finasteride is prepared by dissolving 20.0 g (5α, 17β) -N- (1,1- dimethyl ethyl) -3-oxo-4-aza-androst-2-bromo-17-carboxamide in 60 mL dimethylsulfoxide (DMSO), and a solution of potassium tert-butoxide in DMSO (30.3 g of tert-butoxide in 132 mL of DMSO) at temperature ambient (25 ° C) with stirring until product depletion of departure. Once the reaction is complete, it is neutralized with acid acetic and precipitates on water at 0-5 ° C. Be Filter the precipitate obtained, wash the cake with cold water at 0- 5 ° C and dried in an air oven at 50-55 ° C.

1.2 Obtaining Form I of Finasteride

Polymorphic form I of finasteride was prepared dissolving 10.0 g of finasteride in 160 mL of acetate substantially anhydrous n-butyl (percentage of water 0.03%), at 115 ° C, until completely dissolved. The dissolution of  finasteride was allowed to cool slowly, with a speed of cooling of approximately 0.45 ° C / min, to a temperature 35 ° C, and the resulting suspension was kept under stirring during 3 hours. The solid phase, which contained the crystals of the Form I of finasteride, was collected by filtration and dried at vacuum at approximately 60 ° C. The yield obtained was 76% in weigh.

1.3 Characterization of Finasteride Form I

Polymorphic form I of finasteride previously obtained was characterized by DSC, DRX, IR and thermal analysis.

Registration of exotherm by calorimetry Differential scanning (DSC) was carried out in a dinner capsule, with a heating rate of 10 ° C / min, and revealed the existence of a small endotherm about 236 ° C approximately, extrapolated to baseline of 222 ° C with an associated heat of 12 J / g approximately and a main fusion endotherm at a temperature of approximately 253.2 ° C, with an associated heat of 71 J / g approximately.

X-ray powder diffractogram (DRX) shows characteristic peaks with basal spacing units a 6.39, 5.64, 5.28, 5.13, 4.81, 4.47, 4.30, 3.83, 3.57 and 3.12.

The infrared (IR) spectrum shows some characteristic bands at 3426, 3240, 1687, 1666, 1599, 1504, 814 and 688 cm -1.

Thermal analysis shows that the Product decomposition has two different stages: the first between 250 ° C and 400 ° C with total weight loss and the second at from 400 ° C in which the combustion of the product occurs.

The differential thermal analysis puts manifested a weak exothermic effect of approximately 240 ° C and a weak endothermic effect of approximately 325 ° C, a strong effect endothermic of approximately 385 ° C and, suddenly, a strong exothermic effect that corresponds to the combustion of the product.

The results obtained show that the crystalline form of finasteride obtained is unequivocally Pure Form I

Example 2 Obtaining Form I of Finasteride

Polymorphic form I of finasteride was prepared dissolving 10.0 g of finasteride. in 160 mL of acetate substantially anhydrous n-butyl (percentage of water 0.3%), at 115 ° C, until completely dissolved. The dissolution of finasteride was allowed to cool slowly, with a speed of cooling of approximately 0.45 ° C / min, up to temperature ambient (25 ° C), and the resulting suspension was kept low stirring for 1.5 hours at said temperature. The solid phase, containing the crystals of finasteride Form 1, was collected by filtration and dried under vacuum at approximately 60 ° C. He yield obtained was 75% by weight. The product featured the characteristics indicated in Example 1.3.

Example 3 Obtaining Form I of Finasteride

Polymorphic form I of finasteride was prepared dissolving 10.0 g of finasteride in 160 mL of acetate n-butyl substantially anhydrous (percentage of water  0.03%), at 115 ° C, until completely dissolved. The dissolution of finasteride was allowed to cool slowly, with a speed of cooling of approximately 0.42 ° C / min, up to 30 ° C, and the The resulting suspension was kept under stirring for 1.5 hours. The solid phase, which contained the Form I crystals of finasteride, collected by filtration and dried under vacuum at 60 ° C approximately. The yield obtained was 73% by weight. The product had the characteristics indicated in the Example 1.3.

Example 4 Obtaining Form I of Finasteride

Polymorphic form I of finasteride was prepared dissolving 10.0 g of finasteride in 160 mL of acetate substantially anhydrous n-butyl (percentage of water 0.03%), at 115 ° C, until completely dissolved. The dissolution of  finasteride was allowed to cool slowly, with a speed of cooling of approximately 0.38 ° C / min, up to 45 ° C, and the The resulting suspension was kept under stirring for 2 hours. The solid phase, which contained the crystals of Form 1 of finasteride, collected by filtration and dried under vacuum at 60 ° C  approximately. The yield obtained was 63% by weight. He product had the characteristics indicated in the Example 1.3.

Example 5 Obtaining Form I of Finasteride

Polymorphic form I of finasteride was prepared dissolving 10.0 g of finasteride in 180 mL of acetate substantially anhydrous n-butyl (percentage of water 0.03%), at 115 ° C, until completely dissolved. The dissolution of  finasteride was allowed to cool slowly, with a speed of cooling of approximately 0.46 ° C / min, up to temperature ambient (25 ° C), and the resulting suspension was kept low stirring for 1.5 hours. The solid phase, which contained the Form I crystals of finasteride, collected by filtration and dried under vacuum at approximately 60 ° C. Performance obtained was 74% by weight. The product featured the characteristics indicated in Example 1.3.

Example 6 Obtaining Form I of Finasteride

Polymorphic form I of finasteride was prepared dissolving 10.0 g of finasteride in 140 mL of acetate n-butyl substantially anhydrous (percentage of water  0.03%), at 115 ° C, until completely dissolved. The dissolution of finasteride was allowed to cool slowly, with a speed of cooling of approximately 0.45 ° C / min, up to temperature ambient (25 ° C), and the resulting suspension was kept low stirring for 1.5 hours. The solid phase, which contained the Form I crystals of finasteride, collected by filtration and dried under vacuum at approximately 60 ° C. Performance obtained was 81% by weight. The product featured the characteristics indicated in Example 1.3.

Example 7 Obtaining Form I of Finasteride

Polymorphic form I of finasteride was prepared dissolving 10.0 g of finasteride in 160 mL of acetate substantially anhydrous n-butyl (percentage of water 0.03%), at 115 ° C, until completely dissolved. The dissolution of  finasteride was concentrated in vacuo and allowed to cool slowly, with a cooling rate of approximately 0.45 ° C / min, up to room temperature (25 ° C), and the resulting suspension was maintained under stirring for 1.5 hours. The solid phase, which contained the Form I crystals of finasteride, collected by filtration and dried under vacuum at approximately 60 ° C. Performance obtained was 79% by weight. The product featured the characteristics indicated in Example 1.3.

Example 8 Obtaining Form I of Finasteride

Polymorphic form I of finasteride was prepared dissolving 10.0 g of finasteride in 140 mL of acetate substantially anhydrous n-butyl (percentage of water 0.03%), at 115 ° C, until completely dissolved. The dissolution of  finasteride was allowed to cool slowly, with a speed of cooling of approximately 0.42 ° C / min, up to 35 ° C, and the The resulting suspension was kept under stirring for 1 hour. The solid phase, which contained the crystals of Form I of finasteride, collected by filtration and dried under vacuum at 60 ° C approximately. The yield obtained was 73% by weight. The product had the characteristics indicated in the Example 1.3.

Example 9 Obtaining Form I of Finasteride

Polymorphic form I of finasteride was prepared dissolving 10.0 g of finasteride in 200 mL of acetate n-butyl substantially anhydrous (percentage of water  0.03%), at 115 ° C, until completely dissolved. The dissolution of finasteride was allowed to cool slowly, with a speed of cooling of approximately 0.25 ° C / min, up to 45 ° C, and the The resulting suspension was kept under stirring for 1.5 hours. The solid phase, which contained the Form I crystals of finasteride, collected by filtration and dried under vacuum at 60 ° C approximately. The yield obtained was 70% by weight. The product had the characteristics indicated in the Example 1.3.

Example 10 Obtaining a mixture of crystalline forms of finasteride

10.0 g of finasteride were dissolved in 160 mL of substantially anhydrous n-butyl acetate (0.03% water percentage), at 115 ° C, until completely dissolved. The finasteride solution was allowed to cool slowly, with a cooling rate of about 0.57 ° C / min, up to 0 ° C, and the resulting suspension was kept under stirring for 2 hours. The solid phase was collected by filtration and dried at vacuum at approximately 60 ° C. The yield obtained was 77% in weigh. The product featured on the X-ray diffractogram in Dust (DRX) signals a mixture of crystalline forms.

Example 11 Obtaining a mixture of crystalline forms of finasteride

10.0 g of finasteride were dissolved in 160 mL of substantially anhydrous n-butyl acetate (0.03% water percentage), at 115 ° C, until completely dissolved. The finasteride solution was allowed to cool rapidly, with a cooling rate of 2 ° C / min, up to room temperature (25 ° C), and the resulting suspension was kept under stirring for 2 hours The solid phase was collected by filtration and was dried under vacuum at approximately 60 ° C. The yield obtained was 77% by weight. The product featured on the diffractogram of X-ray powder (DRX) signals of a mixture of forms crystalline

Example 12 Obtaining Form I of Finasteride

Polymorphic form I of finasteride was prepared dissolving 10.0 g of finasteride in 200 mL of acetate substantially anhydrous iso-butyl (percentage of water 0.02%), at 115 ° C, until completely dissolved. Dissolution finasteride was allowed to cool slowly, with a speed of cooling of approximately 0.45 ° C / min, up to temperature ambient (25 ° C), and the resulting suspension was kept low stirring for 3 hours. The solid phase, which contained the Form I crystals of finasteride, collected by filtration and dried under vacuum at approximately 60 ° C. Performance obtained was 77% by weight. The product featured the characteristics indicated in Example 1.3.

Example 13 Obtaining Form I of Finasteride

Polymorphic form I of finasteride was prepared dissolving 10.0 g of finasteride in 200 mL of isoamyl acetate substantially anhydrous (water percentage less than 0.01%), at 130 ° C, until completely dissolved. Finasteride solution allowed to cool slowly, with a cooling rate of approximately 0.70 ° C / min, up to 0 ° C, and the resulting suspension is kept under stirring for 1 hour. The solid phase, which contained the crystals of the form I of finasteride, was collected by filtration and dried under vacuum at approximately 60 ° C. E 1 yield obtained was 80% by weight. The product featured the characteristics indicated in Example 1.3.

Example 14 Obtaining Form I of Finasteride

Polymorphic form I of finasteride was prepared dissolving 10.0 g of finasteride in 570 mL of acetate substantially anhydrous tert-butyl (percentage of water 0.04%), at 95 ° C, until completely dissolved. The dissolution of finasteride was allowed to cool slowly, with a speed of cooling of approximately 0.40 ° C / min, up to temperature ambient (25 ° C), and the resulting suspension was kept low stirring for 16 hours. The solid phase, which contained the Form I crystals of finasteride, collected by filtration and dried under vacuum at approximately 60 ° C. Performance obtained was 72% by weight. The product featured the characteristics indicated in Example 1.3.

Example 15 Crystallization in methyl acetate

10.0 g of finasteride were dissolved in 100 mL of substantially anhydrous methyl acetate (lower percentage of water 0.01%), at 70 ° C, until completely dissolved. The dissolution of finasteride was concentrated in vacuo, allowed to cool slowly until room temperature (25 ° C) and the resulting suspension was maintained under stirring for 1.5 hours. The solid phase was collected by filtration and dried under vacuum at approximately 60 ° C. He yield obtained was 23% by weight. The product did not present in the X-ray powder diffractogram (DRX) signals of Form I of Finasteride

Example 16 Obtaining a mixture of crystalline forms of finasteride

10.0 g of finasteride were dissolved in 570 mL of substantially anhydrous tert-butyl acetate (0.04% water percentage), at 95 ° C, until its complete dissolution. The finasteride solution was allowed to cool slowly, with a cooling rate of about 0.47 ° C / min, up to 0 ° C, and the resulting suspension was kept under stirring for 1 hour. The solid phase was collected by filtration and dried at vacuum at approximately 60 ° C. The yield obtained was 71% in weigh. The product featured on the X-ray diffractogram in Dust (DRX) signals a mixture of crystalline forms.

Example 17 Obtaining a mixture of crystalline forms of finasteride

10.0 g of finasteride were dissolved in 220 mL of substantially anhydrous n-propyl acetate (0.07% water percentage), at 95 ° C, until completely dissolved. The  finasteride solution was allowed to cool slowly, with a cooling rate of approximately 0.37 ° C / min, up to room temperature (25 ° C), and the resulting suspension was maintained under stirring for 2 hours. The solid phase was collected by filtration and dried under vacuum at approximately 60 ° C. Performance obtained was 54% by weight. The product featured in the X-ray powder diffractogram (DRX) signals from a mixture of crystalline forms

Example 18 Obtaining a mixture of crystalline forms of finasteride

10.0 g of finasteride were dissolved in 220 mL of substantially anhydrous n-propyl acetate (0.07% water percentage), at 95 ° C, until completely dissolved. The finasteride solution was allowed to cool slowly, with a cooling rate of about 0.50 ° C / min, up to 0 ° C, and the resulting suspension was kept under stirring for 2 hours. The solid phase was collected by filtration and dried at vacuum at approximately 60 ° C. The yield obtained was 65% in weigh. The product featured on the X-ray diffractogram in Dust (DRX) signals a mixture of crystalline forms.

Example 19 Obtaining a mixture of crystalline forms of finasteride

10.0 g of finasteride were dissolved in 200 mL of substantially anhydrous iso-butyl acetate (0.02% water percentage), at 110 ° C, until completely dissolved. The finasteride solution was allowed to cool slowly, with a cooling rate of approximately 0.55 ° C / min, up to 0 ° C, and the resulting suspension was kept under stirring for 1.5 hours. The solid phase was collected by filtration and dried at vacuum at approximately 60 ° C. The yield obtained was 67% in weigh. The product featured on the X-ray diffractogram in Dust (DRX) signals a mixture of crystalline forms.

Claims (14)

1. A procedure for obtaining the form polymorphic of finasteride called Form I comprising the following stages:

to)

dissolve finasteride in a solvent organic, substantially anhydrous, selected from acetate n-butyl, iso-butyl acetate, sec-butyl acetate, acetate tert-butyl, C5 alkyl acetate, and their mixtures, at a temperature equal to or lower than the boiling point of said organic solvent;

b)

cool finasteride solution obtained in stage a) until:

(i)

a cooling temperature between 20 ° C and 45 ° C, with a cooling rate between 0.1 ° C / min and less than 2 ° C / min, when said organic solvent is acetate n-butyl, iso-butyl acetate, sec-butyl acetate or acetate tert-butyl; Or until

(ii)

a cooling temperature between 0 ° C and 45 ° C, with a cooling rate between 0.1 ° C / min and less than 2 ° C / min, when said organic solvent is alkyl acetate C5; and

C)

keep the suspension resulting from the step b) at the cooling temperature for a period of time equal to or less than 16 hours, optionally with stirring, Y

d)

recover the resulting solid phase that contains Form I of finasteride, and remove the solvent

2. Method according to claim 1, in the that said organic solvent has an equal water content or less than 0.08% (w / w). 3. Method according to claim 1, in the that finasteride dissolves hot at a temperature between 80 ° C and 140 ° C. 4. Method according to claim 1, in the that the cooling rate of finasteride solution It is between 0.2 ° C / min and 1.3 ° C / min. 5. Method according to claim 1, in the that said solvent is n-butyl acetate, iso-butyl acetate, acetate sec-butyl or acetate tert-butyl, and the cooling rate of the finasteride solution is between 0.3 ° C / min and 0.5 ° C / min 6. Method according to claim 1, in the that cooling the hot finasteride solution obtained in step a) is performed with stirring. 7. Method according to claim 1, in the that the finasteride suspension obtained in step b) is keeps at the cooling temperature for a period of Time between 1 and 6 hours. 8. Method according to claim 1, in the that finasteride dissolves in a solvent selected from n-butyl acetate and acetate iso-butyl, at a temperature between 100 ° C and 120 ° C, said solution is allowed to cool with a speed Cooling between 0.2 ° C / minute and 1.3 ° C / minute up to a cooling temperature between 20 ° C and 45 ° C, and maintained at that temperature for a period of time between 1 and 3 hours. 9. Method according to claim 1, in the that finasteride dissolves in acetate tert-butyl at a temperature between 90 ° C and 100 ° C, said solution is allowed to cool with a speed of cooling between 0.2 ° C / minute and 1.3 ° C / minute, up to a cooling temperature between 20 ° C and 45 ° C, and maintained at that temperature for a period of time between 1 and 16 hours. 10. Method according to claim 1, in which finasteride dissolves in isoamyl acetate at a temperature between 120 ° C and 140 ° C, said solution is let cool with a cooling rate between 0.2 ° C / minute and 1.3 ° C / minute, up to a cooling temperature between 0 ° C and 45 ° C, and is maintained at that temperature for a period of time between 1 and 3 hours. 11. Method according to claim 1, in the solid phase that contains the crystals of Form I of Finasteride is recovered by filtration. 12. Method according to claim 1, in which the crystals of finasteride Form I recovered are They undergo a drying process. 13. Method according to claim 1, which it also includes a concentration step of the solution of finasteride obtained in stage a) before recovering the phase solid that contains the crystals of Form I of finasteride. 14. Method according to claim 13, in that the concentration stage of the finasteride solution is performed hot, vacuum, before proceeding to its cooling.